This is a multi-center, open-label, Phase Ib dose escalation / Phase II study in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) patients considered to be resistant, ineligible or intolerant to platinum-based chemotherapy. The first aim of the Phase Ib is to determine the Maximum Tolerated Dose(s) (MTD(s)) and/or the Recommended Phase II Dose(s) (RP2D(s)) for BYL719 in combination with cetuximab This part will include two different arms using two different administration methods of BYL719 tablets together with cetuximab as recommended by the label: Arm A - whole tablets will be administered to patients able to swallow the tablets vs. Arm B - a drinkable suspension prepared from crushed tablets will be administered to patients with swallowing dysfunction. The second aim of the Phase Ib is to compare the pharmacokinetics (PK) of the new dispersible tablet formulation of BYL719 in combination with cetuximab. A third arm will be opened: Arm C, which will use a suspension from a dispersible tablet administered via gastric feeding tube (G tube). The safety, tolerability, PK, PD, and efficacy will be investigated separately in the Phase Ib arms. The MTD/RP2D will only be investigated independently for Arm A and B. The one of Arm B will be compared to that of Arm A. If the MTD/RP2D is the same, then both administration methods of BYL719 may be used in Phase II. If the MTD/RP2D is different, then only the administration of BYL719 whole tablets will be allowed in the Phase II. Arm C is an independent relative bioavailability study of the new dispersible tablet formulation of BYL719, which will begin at the starting dose/RP2D identified with a safety cohort followed by an expansion cohort. There will be no dose escalation or de-escalation in this Arm. If either the safety or pharmacokinetic profile of the RP2D of 300 mg QD in Arm C is not comparable with Arm A, then enrollment in Arm C will cease and the dispersible tablet will not be implemented in Phase II.

The Phase Ib dose escalation part is expected to enroll approximately 12 patients for Arm A and B and will be guided by a Bayesian logistic regression model (BLRM). The available safety, tolerability, PK, PD and efficacy data, as well as the recommendations from the BLRM, are used to determine the dose combination for the next cohort(s). The Phase II part of the study will commence upon MTD/RP2D declaration of Arm A in Phase Ib, regardless of the progress of Arm B and C.

The Phase II part will assess the clinical efficacy of BYL719 in combination with cetuximab in two patient populations: patients will be assigned to one of two schemes of enrollment based on prior therapy with cetuximab.

Patients considered cetuximab naïve per protocol will be assigned to Scheme 1. The primary purpose of this scheme is to assess the anti-tumor activity of BYL719 in combination with cetuximab (Arm 1) vs. cetuximab as single-agent (Arm 2) in RM HNSCC patients' naïve to cetuximab. Patients in scheme 1 will be randomized in a 2:1 ratio via IRT in two Phase II arms: BYL719 in combination with cetuximab (Arm 1) vs. cetuximab as single-agent (Arm 2). Patients randomized to Arm 2 (cetuximab monotherapy) will have the opportunity to cross-over to combination treatment with BYL719 + cetuximab after experiencing disease progression. Arm 1 will consist of approximately 66 patients and Arm 2 of approximately 33 patients.

Patients having received prior cetuximab per protocol will be assigned to Scheme 2. The primary purpose of this scheme is to assess the anti-tumor activity of BYL719 in combination with cetuximab in RM HNSCC cetuximab resistant patients (Arm 3). Patients in this scheme will not be randomized. 40 patients will be enrolled. Phase II will further characterize the safety and PK of the drug combination.

Patients will be treated until progression of disease (except for phase II Arm 2), unacceptable toxicity, or withdrawal of informed consent, whichever occurs first. Patients enrolled in Arm 2 experiencing disease progression will have the opportunity to crossover to the combination treatment (Arm 2B) and they will continue until they experience unacceptable toxicity that precludes any further treatment, until disease progression, and/or until treatment is discontinued at the discretion of the Investigator or by patient refusal. In the follow-up period all patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment. Patients who have not progressed at the time of discontinuation of study treatment should be radiologically followed for disease status until disease progression, initiation of subsequent anticancer therapies, or death, whichever occurs first. In addition, all patients enrolled in Phase II will be followed for survival.

Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (RM HNSCC) Patients Who Are Resistant or Ineligible/Intolerant to Platinum-based Chemotherapy.
Recurrent Head and Neck Squamous Cell Carcinoma
Metastatic Head and Neck Squamous Cell Carcinoma

Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets) and arm B (BYL719 administered as a drinkable suspension in patients with swallowing dysfunction)

Phase II, Scheme 2 (Arm 3): To further assess the anti-tumor activity of the BYL719 in combination with cetuximab in RM HNSCC patients who have progressed following treatment with cetuximab and platinum

Phase II, Scheme 2 (Arm 3): To further assess the anti-tumor activity of the BYL719 in combination with cetuximab in RM HNSCC patients who have progressed following treatment with cetuximab and platinum

Phase II, Scheme 2 (Arm 3): To further assess the anti-tumor activity of the BYL719 in combination with cetuximab in RM HNSCC patients who have progressed following treatment with cetuximab and platinum

BYL719 + cetuximab in patients resistant to cetuximab. BYL719 can be administered as FC whole/crushed only or DT via G-tube in addition, depending on the Phase Ib results

Drug: BYL719 as film-coated (FC) whole tablets

Oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Drug: BYL719 as dispersible tablets (DT)

New formulation of the oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Biological: cetuximab

Recombinant chimeric monoclonal antibody driven against EGFR

Other Name: erbitux

Drug: BYL719 as film-coated (FC) drink suspension

Oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Experimental: Phase II: 1-BYL719 + Cetuximab

BYL719 + Cetuximab in Patients naive to cetuximab. BYL719 can be administered as FC whole/crushed only or DT via G-tube in addition, depending on the Phase Ib results

Drug: BYL719 as film-coated (FC) whole tablets

Oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Drug: BYL719 as dispersible tablets (DT)

New formulation of the oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Biological: cetuximab

Recombinant chimeric monoclonal antibody driven against EGFR

Other Name: erbitux

Drug: BYL719 as film-coated (FC) drink suspension

Oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Experimental: Phase Ib: C-BYL719 DT+cetux

Via gastrostomy tube (G-tube)

Drug: BYL719 as dispersible tablets (DT)

New formulation of the oral alpha-specific PI3K inhibitor

Other Name: NVP-BYL719

Biological: cetuximab

Recombinant chimeric monoclonal antibody driven against EGFR

Other Name: erbitux

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Age ≥ 18 years

Patients with histologically/cytologically-confirmed HNSCC

Patients must be resistant to platinum-based chemotherapy, or be ineligible (due to medical comorbidities) or intolerant to platinum-based therapy per medical history

For Phase Ib, there is no restriction on the number of prior therapies for recurrent or metastatic disease

For Phase II, patients may have received a maximum of 1 prior line of therapy for recurrent or metastatic disease

For Phase Ib, prior cetuximab or other EGFR-targeted antibody therapy is allowed regardless of the prior treatment settings.

For Phase II, Arms 1 and 2, prior cetuximab or other EGFR-targeted antibody therapy is allowed only if administered in the induction setting, or concurrently with radiation in the curative setting, with the last dose of cetuximab administered at least 12 months prior to starting the study treatment. For Arm 3, prior cetuximab must have been administered in the curative, recurrent or metastatic disease setting and disease progression documented within 9 months of the last dose of cetuximab administered in that setting. This regimen (including both platinum and cetuximab) must be the most recent anti-neoplastic treatment regimen administered.

Patients with swallowing dysfunction who are unable to swallow BYL719 whole tablets and are not using feeding tubes for study drug administration can participate in the Phase Ib Arm B. For the Phase II, these patients with swallowing dysfunction may participate if able to drink the suspension and results of Arm B confirm the use of this method. Patients with swallowing dysfunction requiring G tube (G/PEG tube) for study drug administration may participate in Phase II if Arm C confirms dispersible tablet via G tube administration is permitted if the administration of drinkable suspension of BYL719 is allowed to be used in Phase II.

Availability of a representative tumor specimen. Patients enrolled in Arm 3 of Phase II must have disease sites amenable to biopsy unless prior agreement between Novartis and the Investigator.

At least one measurable or non-measurable lesion as per RECIST 1.1 criteria for patients in Phase Ib; Measurable disease as determined by RECIST v1.1 for Phase II patients

World Health Organization (WHO) Performance Status (PS) ≤ 2

Adequate organ function

Negative serum pregnancy test.

Exclusion Criteria:

Prior treatment with PI3K-inhibitors

Patients with a prior serious infusion reaction to cetuximab

Patients with uncontrolled CNS tumor metastatic involvement

Clinically significant cardiac disease or impaired cardiac function

Patients with diabetes mellitus

Impaired GI function or GI disease

History of another malignancy within 2 years prior to starting study treatment

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01602315